Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Ng, KW; Boumelha, J; Enfield, KSS; Almagro, J; Cha, H; Pich, O; Karasaki, T; Moore, DA; Salgado, R; Sivakumar, M; Young, G; Molina-Arcas, M; de Carne Trecesson, S; Anastasiou, P; Fendler, A; Au, L; Shepherd, STC; Martinez-Ruiz, C; Puttick, C; Black, JRM; Watkins, TBK; Kim, H; Shim, S; Faulkner, N; Attig, J; Veeriah, S; Magno, N; Ward, S; Frankell, AM; Al Bakir, M; Lim, EL; Hill, MS; Wilson, GA; Cook, DE; Birkbak, NJ; Behrens, A; Yousaf, N; Popat, S; Hackshaw, A; TRACERx Consortium; CAPTURE Consortium; Hiley, CT; Litchfield, K; McGranahan, N; Jamal-Hanjani, M; Larkin, J; Lee, SH; Turajlic, S; Swanton, C; Downward, J; Kassiotis, G

Author(s): Ng, KW; Boumelha, J; Enfield, KSS; Almagro, J; Cha, H; Pich, O; Karasaki, T; Moore, DA; Salgado, R; Sivakumar, M; Young, G; Molina-Arcas, M; de Carne Trecesson, S; Anastasiou, P; Fendler, A; Au, L; Shepherd, STC; Martinez-Ruiz, C; Puttick, C; Black, JRM; Watkins, TBK; Kim, H; Shim, S; Faulkner, N; Attig, J; Veeriah, S; Magno, N; Ward, S; Frankell, AM; Al Bakir, M; Lim, EL; Hill, MS; Wilson, GA; Cook, DE; Birkbak, NJ; Behrens, A; Yousaf, N; Popat, S; Hackshaw, A; TRACERx Consortium; CAPTURE Consortium; Hiley, CT; Litchfield, K; McGranahan, N; Jamal-Hanjani, M; Larkin, J; Lee, SH; Turajlic, S; Swanton, C; Downward, J; Kassiotis, G;
Details: Publication Year 2023-04,Volume 616,Issue #7957,Page 563-573
Journal Title: Nature
Publication Type: Research article
Abstract: B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)(1,2). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive(1,2). Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma(3). We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Publisher: Springer Nature
Keywords: Animals; Humans; Mice; Adenocarcinoma of Lung/immunology/therapy/virology; Carcinoma, Non-Small-Cell Lung/immunology/therapy/virology; Disease Models, Animal; *Endogenous Retroviruses/immunology; *Immunotherapy/methods; Lung/immunology; *Lung Neoplasms/immunology/therapy/virology; Tumor Microenvironment; B-Lymphocytes/immunology; Cohort Studies; Antibodies/immunology/therapeutic use
Department(s): Laboratory Research
PubMed ID: 37046094
Publisher's Version: https://doi.org/10.1038/s41586-023-05771-9
Open Access at Publisher's Site: https://doi.org/10.1038/s41586-023-05771-9
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-03 07:58:27

Last Modified: 2023-08-03 08:01:33